The Good Pharmacovigilance Practice (GVP) Guideline 'Product- or Population-Specific Considerations IV: Paediatric Population' came into effect on 08 November 2018. It forms part of the European Medicines Agency (EMA) GVP modules and associated documentation which can be found here.
QVigilance has reviewed this GVP document and notes the following key points:
- The guidance should be used in conjunction with Title IV (post-authorisation requirements) of the Paediatric Regulation (Article 34), Regulation (EC) No. 726/2004 and Directive 2001/83/EC.
- It does not replace any of the guidance provided in GVP Modules I to XVI and should be used in conjunction with these.
- Paediatric use of vaccines and paediatric outcomes after exposure in utero are out of scope for this guidance and are covered in GVP ‘Product- or population-specific considerations I: Vaccines for prophylaxis against infectious diseases (effective since 13 December 2013) and GVP Product or population specific considerations III: Pregnancy and breastfeeding (pending release).
- It covers the following medicines:
- Medicines with a paediatric indication
- Medicines with an adult indication that are being developed for paediatric use
- Medicines with an adult indication that are being used in the paediatric population
The guidance covers the following key points:
- Definitions of the paediatric population (including subgroups)
- Key aspects of Pharmacovigilance (PV) specific to paediatric populations
- Individual Case Safety Reports (ICSRs)
- Periodic Safety Update Reports (PSURs)
- Risk Management Plan (RMP)
- Signal Management
- Safety Communication
- Paediatric Investigation Plan (PIP)
Definition of Paediatric Population
The paediatric population is defined in the European Union (EU) as “that group of population between birth and 18 years of age”.
It is further sub-divided into the following groups:
|Pre-term new born neonates||Day of birth through the expected date of delivery (EDD) plus 27 days|
|Term and post-term neonates||Day of birth plus 27 days|
|Infants||1 month [28 days] to 23 months|
|Children||2 to 11 years|
|Adolescents||12 to less than 18 years|
Key Aspects of PV Relating to Paediatric Populations
- Susceptibility to adverse reactions (ARs) differs from the adult population due to various factors including:
- Different physiology – Pharmacokinetic (PK) and Pharmacodynamic (PD) differences to adults
- Absorption, Distribution, Metabolism and Excretion (ADME) of an active substance may be different in paediatric populations (especially within the younger paediatric sub-groups)
- Growth and development stages
- Immaturity of some organ systems
- Immunological differences as a result of the immaturity of the immune system
- Differences within the paediatric sub-groups (within the paediatric population as a whole)
- Long-term exposure effects
- Limited number of patients in paediatric clinical trials, leading to a lack of authorised products specifically approved for paediatric use
- Widespread off-label use can lead to an increased risk of medication errors and ARs
- Clinical presentation of ARs can be significantly different in the paediatric population as a whole (when compared to adults) but may also differ between the different sub-groups
- Communication ability – this is especially important to recognise and address within the different sub-groups (e.g. how pain or other feelings of discomfort are manifested or described by the paediatric patient)
Paediatric considerations for ICSRs:
- A medicinal product may be used off-label and data collected may be instrumental in identifying new, more specific and/or more serious ARs that have not been previously observed in the population that the product is authorised for.
- ICSRs should be as complete as possible (whether used for an approved indication or off-label).
- The following information is particularly relevant for paediatric populations:
- Age information (should be as accurate as possible)
- Information on maternal or paternal exposure during pregnancy, via breastfeeding, birth history and developmental parameters
- Indication (i.e. authorised for the paediatric populations, off-label or a medication error)
- Pharmaceutical form and strength
- Dosage (prescribed and/or administered) and dosing regimen
- Weight and height at the time of the AR
Paediatric considerations for PSURs:
- PSURs should address the following:
- Any new safety issues identified in the paediatric population as a whole but also by sub-groups
- Off-label use, including use of not age-appropriate formulations or use in paediatric sub-groups for which the product is not authorised
- Identified signal of a paediatric AR
- Information on the number of paediatric patients exposed during the reporting interval and method of exposure by patient sub-groups
- Safety findings from on-going or completed paediatric trials
- Note: the addition of a paediatric indication to an for an authorised product may lead to a request for a higher frequency of PSUR submissions.
Paediatric considerations for the RMP:
- Methods used to minimise the risk of ARs in the adult population should be evaluated and adapted to meet aspects specific to the paediatric population.
- Data gained from clinical studies in the adult population should be used to support identification of important potential risks in the paediatric population.
- RMPs should be tailored to include the key aspects of PV specific to the paediatric population, as aforementioned.
- If risks that may be specific to the paediatric population are highlighted, a paediatric specific Post Authorisation Safety Study (PASS) may be required.
- The availability of data (including pre-clinical data), based on previous exposure, may be varied or limited.
- If it is not anticipated that a specific sub-group of the paediatric population will be different from an adult population (e.g. based on a sub-group such as post-pubertal), this needs to be supported by evidence that is disclosed at the time of the marketing authorisation (MA) application.
Paediatric considerations for Signal Management:
- Signal Management activities should focus on the expected differences when compared to adults.
- ICSR analysis should be performed separately, distinguishing between adult and paediatric patients (and sub-groups of paediatric patients).
Paediatric considerations for Safety Communications:
- Safety communications should be compiled in a way that accounts for the different paediatric sub-groups and should take into consideration that paediatric patients may be involved in the decision making process regarding therapeutic options for their condition.
- MA holders and National Competent Authorities (NCAs) need to be mindful that when compiling any safety communications and/or supporting educational materials about medicinal products, the target audience may include paediatric patients.
- Communications should be age appropriate and take into account different media channels and the presentation of information.
- Health Care Professionals involved in the therapeutic decision making process need to be fully aware and informed, so that they can discuss treatment options and outcomes effectively with the child (as appropriate) and/or parent/carer or legal representative. In particular consideration should be given to providing adequate information about any impact on growth and development, cognitive and sexual/reproductive functions and potential long-term effects.
- A PIP is defined as a “research and development programme aimed at ensuring that the necessary data are generated determining the conditions in which a medicinal product may be authorised to treat the paediatric population”.
- It may include the following:
- Interventional studies
- Non-interventional studies
- Non-clinical studies
- Extrapolation studies
- Modelling and simulation studies
- Development of specific paediatric pharmaceutical formulations
- The requirement for a PIP also applies if the MA holder wants to add a new indication, pharmaceutical form or route of administration for a product that is already authorised.
- The Paediatric Committee (PDCO) is responsible for assessing the content of PIPs (including assessing applications for waivers and study deferrals).
- The PDCO work collaboratively with the Pharmacovigilance Risk Assessment Committee (PRAC).
- Paediatric patients are not just smaller versions of adults and there are very specific aspects to PV activities that need to be taken into consideration.
- Adults often need to make a decision or advise, on behalf of children, about treatment options and so it is vital that they are fully informed about the potential risks specific to paediatric patients when engaging in discussions about therapeutic options.
European Medicines Agency, 2018, (Guideline on good pharmacovigilance practices (GVP)
Product- or Population-Specific Considerations IV: Paediatric population), European Medicines Agency. Accessed: September 2019. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-product-population-specific-considerations-iv_en-0.pdf